Acute Myleloid Leukemia (AML) represents a paradigm for understanding how complex patterns of cooperating genetic and epigenetic alterations lead to tumorigenesis. While this complexity poses a challenge for the development of targeted therapy, diverse AML gene mutations generally converge functionally in deregulating similar core cellular processes. One key event in AML initiation is the corruption of cell-fate programs to generate Leukemic Stem Cells (LSCs) that aberrantly self-renew and thereby maintain and propagate the disease. While incompletely understood, this process has been linked to changes in regulatory chromatin modifications whose impact on gene expression is well characterized. Hence, common oncogenes in AML, such as AML1-ETO and MLL fusion proteins induce self-renewal programs, at least in part, through reprogramming of epigenetic pathways. Several epigenetic regulators are targets of somatic mutation. Since epigenetic alterations induced by oncogenic stimuli are potentially reversible, chromatin regulators are being explored as candidate drug targets.